This invention is in the field of anticoagulant therapy, and specifically relates to compounds, compositions and methods for preventing and treating thrombotic conditions such as coronary artery and cerebrovascular disease. More particularly, the invention relates to substituted polycyclic aryl and heteroaryl pyridine compounds, and prodrugs thereof, that inhibit serine proteases of the coagulation cascade.
Hemorrhage, intravascular thrombosis, and embolism are common clinical manifestations of many diseases [see R. I. Handin in Harrison""s Principles of Internal Medicine (J. D. Wilson, et al. eds., 12th ed. 1991) New York, McGraw-Hill Book Co., pp. 348-351]. The normal hemostatic system limits blood loss by precisely regulated interactions between components of the vessel wall, circulating blood platelets, and plasma proteins. However, unregulated activation of the of the hemostatic system may cause thrombosis, which can reduce blood flow to critical organs like the brain and myocardium. Physiological systems control the fluidity of blood in mammals [see P. W. Majerus, et al. in Goodman and Gilman""s The Pharmacological Basis of Therapeutics (J. G. Hardman and L. E. Limbird, eds., 9th ed. 1996) New York, McGraw-Hill Book Co., pp. 1341-1343]. Blood must remain fluid within the vascular systems and yet quickly be able to undergo hemostasis. Hemostasis, or clotting, begins when platelets first adhere to macromolecules in subendothelian regions of injured and/or damaged blood vessels. These platelets aggregate to form the primary hemostatic plug and stimulate local activation of plasma coagulation factors leading to generation of a fibrin clot that reinforces the aggregated platelets.
Plasma coagulation factors, also referred to as protease zymogens, include factors II, V, VII, VIII, IX, X, XI, and XII. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called xe2x80x9ccoagulation cascadexe2x80x9d or chain reaction.
Coagulation or clotting occurs in two ways through different pathways. An intrinsic or contact pathway leads from XII to XIIa to XIa to IXa and to the conversion of X to Xa. Xa with factor Va converts prothrombin (II) to thrombin (IIa) leading to conversion of fibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot. An extrinsic pathway is initiated by the conversion of coagulation factor VII to VIIa by Xa. Factor VIIa, a plasma protease, is exposed to, and combines with its essential cofactor tissue factor (TF) which resides constitutively beneath the endothelium. The resulting factor VIIa/TF complex proteolytically activates its substrates, factors IX and X, triggering a cascade of reactions that leads to the generation of thrombin and a fibrin clot as described above.
While clotting as a result of an injury to a blood vessel is a critical physiological process for mammals, clotting can also lead to disease states. A pathological process called thrombosis results when platelet aggregation and/or a fibrin clot blocks (i.e., occludes) a blood vessel. Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery. When the thrombosis occurs in a coronary artery, a myocardial infarction or heart attack can result. A thrombosis occurring in a vein may cause tissues drained by the vein to become edematous and inflamed. Thrombosis of a deep vein may be complicated by a pulmonary embolism. Preventing or treating clots in a blood vessel may be therapeutically useful by inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, inhibiting embolus formation, and for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels.
In order to treat such conditions, researchers have sought to discover chemical compounds that efficaciously and selectively control the clotting process. In addition, such compounds may provide a better understanding of the pathways involved in the coagulation process.
Thus far, many of the compounds that have been discovered possess a polar or basic functional group which is integrally responsible for the desired biological activity. Frequently, this polar functional group is a nitrogen atom of, for example, a guandine, alkyl-amidine or aryl-amidine group. Because these functionalities are highly basic, they remain protonated at physiologically relevant pH""s. The ionic nature of such protonated species hinders their permeability across lipophilic membranes, which can reduce bioavailability when the pharmaceutical agent is administered orally.
In order to circumvent such a problem, it is often advantageous to perform a derivatization or chemical modification of the polar functionality such that the pharmaceutical agent becomes neutrally charged and more lipophilic, thereby facilitating absorption of the drug. However, for the derivatization to be useful, the derivatization must be bioconvertable at the target site or sites of desired pharmacological activity and cleaved under normal physiological conditions to yield the biologically active drug. The term xe2x80x9cprodrugxe2x80x9d has been used to denote such a chemically modified intermediate.
There have been limited reports of non-peptidic and peptidic pyridine compounds that act as an inhibitor of a coagulation factor present in the coagulation cascade or clotting process. In PCT Patent Application WO 00/039102, Wexler et al. describe certain 3,5-unsubstituted, 3,5-dichloro, 3-fluoro-5-chloro, 3-chloro-5-fluoro, and 3,5-difluoro pyrid-2-ylacetamides that are further substituted at the 6-position by several groups including several substituted aminos and reported to be inhibitors of trysin-like serine protease enzymes, especially factor Xa and thrombin. There have been reports of non-peptidic benzene compounds that act as an inhibitor of a coagulation factor present in the coagulation cascade or clotting process. In PCT Patent Applications WO 99/00121 and WO 99/00128, Beight et al. describe benzenes that may be fully substituted by substituents that include acylamido, acyloxy, carboxamido, alkoxy, acetamide, carbonates, carbamates, ureas, and other groups and having inhibitory activity against factor Xa. In U.S. Pat. No. 5,872,138 and PCT Patent Application WO 98/10763, Naylor-Olsen et al. describe disubstituted benzenes having a group linked through an oxygen, nitrogen or sulfur heteroatom, any one of six basic heterocycles linked to the ring through linker group, and, optionally, an additional alkyl, alkenyl, alkoxy, amino, or arylmethylenesulfonamido group and claimed to inhibit human thrombin. In PCT Patent Application WO 99/26920, Semple et al. disclose 1-oxy-2,3,4,5-tetrasubstitutedphenylacetamides having an acyl function in the group substituting the amide nitrogen and having activity against thrombin. In PCT Patent Application WO 96/39380, Lu and Soll describe bis-(sulfonamido substitutedbenzoyl) derivatives of diamines claimed to have utility as inhibitors of thrombotic disorders. In PCT Patent Application WO 96/40100, Illig et al. describe sulfonamido substitutedbenzoyl and benzyl derivatives of amines directed to non-peptidic factor Xa and claimed to have utility as inhibitors of thrombotic disorders.
Among the objects of the present invention, therefore, is the provision of compounds useful for selective inhibition of certain enzymes that act upon the coagulation cascade thereby preventing and treating thrombotic conditions in mammals.
Another object of the present invention is the provision of prodrug compounds useful for selective inhibition of certain enzymes that act upon the coagulation cascade thereby preventing and treating thrombotic conditions in mammals. In general, these prodrug compounds undergo hydrolysis, oxidation, reduction or elimination at a derivatized amidine group to yield the active compound.
Briefly, therefore, the present invention is directed to the compound, per se, to the prodrug of the compound, to pharmaceutical compositions comprising the compound or prodrug and a pharmaceutically acceptable carrier, and to methods of use. The compound corresponds to Formula A: 
wherein
X1, X2, X3, X4, X5, and X6 are each ring atoms defining a 6 membered heterocyclic or aromatic ring;
X1, X2, and X4 are independently carbon or nitrogen;
X3 is carbon;
X5 and X6 are independently carbon, nitrogen, oxygen or sulfur, provided at least one of X1, X4, and X6 is other than carbon when X2 is carbon;
L1, L3 and L4 are linkages through which Z1, Z3, and Z4, respectively, are covalently bonded to different ring atoms of the 6 membered heterocyclic or aromatic ring defined by X1, X2, X3, X4, X5, and X6, wherein Z1 is covalently bonded to X1, Z3 is covalently bonded to X3, and Z4 is covalently bonded to X4, each of L1, L3 and L4 independently being a covalent bond or comprising one or more atoms through which Z1, Z3, and Z4 are covalently bonded to X1, X3 and X4, respectively;
Z3 is a substituted hydrocarbyl, or a 5 or 6 membered substituted heterocyclic or aromatic ring, the substituents of the hydrocarbyl or ring comprising an amidine, guanidine, amino, or aminoalkyl group, the ring atoms of the 5 or 6 membered heterocyclic or aromatic ring of Z3 being carbon, sulfur, nitrogen, or oxygen, wherein the 5 or 6 membered ring is optionally substituted at any position with halogen, hydroxy, or alkyl;
Z4 comprises hydrocarbyl, substituted hydrocarbyl or a 5 or 6-membered heterocyclic ring, the ring atoms of the 5 or 6-membered heterocyclic ring being carbon, sulfur, nitrogen or oxygen;
Z1 is hydrogen, hydrocarbyl, or substituted hydrocarbyl; and
Z2 is a hydrogen bond acceptor covalently or datively bonded to X2.
Other objects and features of this invention will be in part apparent and in part pointed out hereafter.